PROJECT ABSTRACT Dr. Zsuzsanna McMahan is an Assistant Professor of Medicine in the Division of Rheumatology at Johns Hopkins University. She obtained her Masters in Clinical Investigation during her rheumatology fellowship training, and she is currently supported by the Johns Hopkins Clinician Scientist Development Award, the Jerome L. Greene Foundation, and the NIH Loan Repayment Program. Her co-primary mentors are Dr. Fredrick Wigley, an internationally recognized rheumatologist with expertise in scleroderma (SSc), and Dr. Livia Casciola-Rosen, an internationally recognized cell biologist with expertise in the identification of novel autoantibodies. Dr. Antony Rosen, the Director of the Division of Rheumatology, and Vice Dean for Research at Johns Hopkins, has significant expertise in translational investigation, and is also part of her mentoring team. Dr. McMahan created an outstanding Advisory Committee comprised of mentors and consultants who have specific areas of expertise which are relevant to the proposal. These include Drs. Michelle Petri (longitudinal cohorts) and Clifton Bingham (patient reported outcomes) in rheumatology, Dr. James Russell in neurology (autonomic dysfunction), and Dr. Jay Pasricha in gastroenterology (dysmotility). They will provide guidance specific to their area(s) of expertise. This Advisory Committee is highly enthusiastic about the proposal and fully invested in mentoring Dr. McMahan. The K23 award will enable Dr. McMahan to gain additional skills important for the conduct of translational research, develop expertise in the specific niche of neurogastroenterology as it pertains to SSc, and acquire the data and publications necessary to support a strong R01 application. In this proposal, Dr. McMahan seeks to precisely define anatomical subsets of SSc gastrointestinal (GI) dysmotility using a radionucleotide-based whole gut transit study, associate the GI dysmotility subsets with traditional SSc antibodies and antibodies that target neuromuscular transmission pathways, and finally define novel autoantigens targeted by SSc sera in the GI tract. Autoantibodies in SSc associate tightly with clinical phenotypes and serve as useful markers in risk stratification. Currently, risk stratification in SSc GI disease is limited, with few autoantibodies associated with GI complications. Clearly phenotyping GI subsets will provide a platform to study disease mechanism within more homogenous SSc GI subsets and provide a framework from which to explore novel therapies in the longer term. Dr. McMahan has generated strong preliminary data, which supports the following ideas: (1) specific patterns of GI dysmotility exist in SSc; (2) autoantibodies to neuromuscular transmission pathways are present in patients with SSc and may associate with specific GI outcomes; and (3) SSc sera from patients with dysmotility recognize distinct cellular subsets in the GI tract. She has established strong inter-departmental collaborations that will provide the required support and expertise to guide her and ensure the completion and appropriate interpretation of the proposed studies. The results of these studies will create a platform for future work aimed at evaluating biological mechanism, defining biomarkers of disease activity, and exploring novel therapies.